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Study Finds New Celiac Disease Risk Factor

Researchers have identified a common variant in a noncoding RNA that may contribute to the intestinal inflammation that occurs in people with celiac disease. The findings, published in Science, point to a possible new risk factor for developing celiac disease in people with celiac disease risk genes.

An estimated 40% of the population has the primary gene variant associated with celiac disease, but only 1% of people with these genes go on to develop intestinal inflammation and damage—the hallmarks of the disease—after ingesting gluten.

"We don't know why only a fraction of individuals with genetic risk factors for celiac disease actually become gluten intolerant," says Peter Green, MD, the Phyllis and Ivan Seidenberg Professor of Medicine at Columbia University Medical Center (CUMC), director of the Celiac Disease Center at Columbia University and coauthor of the study. "It is only through the dedicated work of translational scientists that we can begin to uncover the mechanisms that unleash the symptoms of celiac disease."

Recently, researchers have focused on the ability of noncoding RNA, the portion of our genome that doesn't encode for the production of proteins, to regulate a variety of biological processes. Long noncoding RNA (lncRNA), which contains more than 200 nucleotides, are thought to play a role in autoimmune diseases and cancers by interacting with other RNA, DNA, and proteins. However, it wasn't clear whether changes in lncRNA genes could put people at risk of developing complex diseases in the same way that changes in protein-coding genes do.

Through a variety of experiments, the researchers demonstrated that lnc13 dampens the expression of celiac-associated genes by binding to a common family of proteins. The celiac-associated variant of lnc13 binds poorly to these proteins, leading to increased expression of inflammatory genes. The researchers then discovered that patients with celiac disease had unusually low levels of lnc13 in their intestines, suggesting that downregulation of this gene may contribute to the inflammation seen in celiac disease.

"These findings add an important detail to our understanding about how celiac disease develops," says Sankar Ghosh, PhD, the Silverstein and Hutt Family Professor of Microbiology and Immunology, chairman of the department of microbiology and immunology at CUMC, and lead author of the study. "Given that the majority of the population consumes these grains, understanding the factors that put certain individuals at greater risk of the development of celiac disease will have a broad impact. In future studies, we hope to investigate factors that lead to suppression of lnc13, which may cause celiac disease in people who were previously able to tolerate gluten."